EU/3/08/572

Orphan designation

On 7 November 2008, orphan designation (EU/3/08/572) was granted by the European Commission to Incyte Corporation Ltd, United Kingdom, for (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate for the treatment of chronic idiopathic myelofibrosis.

The sponsorship was transferred to Novartis Europharm Limited, United Kingdom, in September 2010.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

Chronic idiopathic myelofibrosis is a disease in which cancer cells are found in the blood and in the bone marrow. The bone marrow is the spongy tissue inside the large bones in the body. Normally the bone marrow makes cells called 'blasts' that mature into several different types of blood cell that have specific functions in the body. These include red cells, white cells and platelets. Red blood cells carry oxygen and other materials to all tissues of the body. White blood cells fight infection. Platelets make the blood clot. When myelofibrosis develops, the bone marrow produces large number of abnormal blood cells. In chronic idiopathic myelofibrosis, the abnormal population of cells produces substances that alter the growth media of bone marrow and makes bone marrow very dense and rigid. As the abnormal bone-marrow environment is no more adequate for the cells, some migrate to other sites where proliferation and maturation take place.

Chronic idiopathic myelofibrosis is life-threatening, in particular due to the decreased life expectancy of patients.

At the time of designation, chronic idiopathic myelofibrosis affected less than 0.5 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 25,000 people*, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union (EU 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 502,800,000 (Eurostat 2008).

At the time of submission, hydroxyurea was authorised in the Community for the treatment of the condition. Other drugs were used for the treatment of symptoms of the disease such as androgen, glucocorticoids or erythropoietin for anaemia. Splenectomy (surgical removal of the spleen) was performed in case of excessive enlargement of the spleen (splenomegaly), and bone-marrow transplantation in some patients.

Protein kinases are enzymes that regulate many functions in the cell. In chronic idiopathic myelofibrosis, a chain of these molecules are involved in the development of the disease. This is known as the Janus-kinase (JAK) pathway. The product is an inhibitor of the JAK pathway and, by doing this, it is expected to inhibit the development of the disease and reverse some of the negative consequences derived form the condition.

The effects of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with chronic idiopathic myelofibrosis were ongoing.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 10 September 2008 recommending the granting of this designation.

Update: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate (Jakavi) was authorised in the EU since 23 August 2012 for treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia-vera myelofibrosis or post-essential-thrombocythaemia myelofibrosis.

the existence of alternative methods of diagnosis, prevention or treatment;

either the rarity of the condition (affecting not more than 5 in 10,000 people in the European Union) or insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.

Review of designation

During its meeting of 10-11 May 2012, the Committee for Orphan Medicinal Products (COMP) reviewed the designations EU/3/08/572 and EU/3/09/620 for Jakavi (ruxolitinib1) as an orphan medicinal product for the treatment of chronic idiopathic myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the conditions, and the existence of other satisfactory methods of treatment. As other satisfactory methods of treatment for patients with chronic idiopathic myelofibrosis are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. The COMP recommended that the orphan designation of the medicine be maintained2.

1 At time of orphan designation, ruxolitinib was known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate.
2 The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation, similar products with a comparable therapeutic indication cannot be placed on the market.

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Jakavi for 'the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia-vera myelofibrosis or post-essential-thrombocythaemia myelofibrosis'.

This falls within the scope of the product’s designated orphan conditions, which are ‘chronic idiopathic myelofibrosis’ and ‘myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia’.

The COMP concluded that there had been no change in the seriousness of the conditions since the orphan designations in 2008 and 2009. Chronic idiopathic myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia are conditions that are debilitating in the long term and life-threatening, particularly due to the development of pancytopenia (low blood cell count), splenomegaly (enlarged spleen), hepatomegaly (enlarged liver) and leukaemia.

The sponsor provided recent scientific literature on the prevalence of chronic idiopathic myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia in the EU. On the basis of this information and the knowledge of the COMP, the COMP concluded that the prevalence of these conditions remained below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence for chronic idiopathic myelofibrosis was estimated to be approximately 0.3 people in 10,000, and for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia it was estimated to be less than 0.3 people in 10,000. This is equivalent to a total of around, or fewer than, 15,000 people in the EU for each condition, respectively.

At the time of the review of the orphan designation, hydroxycarbamide and busulfan were authorised in the EU for chronic idiopathic myelofibrosis, but there were no treatments authorised specifically for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia. Medicines were authorised to treat the symptoms of these diseases, including erythropoietin to treat anaemia, and surgery or radiation were used to remove or shrink the enlarged spleen.

The COMP noted that, for myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia, no justification of significant benefit over existing treatments was needed as no alternative treatments were authorised in the EU at time of the review.

Regarding the treatment of chronic idiopathic myelofibrosis, the COMP noted that Jakavi works in a different way to authorised treatments, inhibiting enzymes known as Janus kinases (JAKs) 1 and 2, which are known to be overactivated in patients with this condition. More importantly, the COMP noted that in two main phase-III studies, the medicine significantly reduced spleen volume and improved the symptoms of the disease compared with placebo or best available treatment. In the first study, which compared Jakavi with placebo, the significant benefit of the medicine was demonstrated by its efficacy in patients who could not be treated or did not respond to other available treatments. The second study showed improved efficacy of Jakavi as compared with best available treatments. In particular, 29% of patients receiving Jakavi experienced a reduction in spleen size by at least 35% following 48 weeks of treatment, compared with zero patients receiving best available treatment.

Therefore, although other satisfactory methods for the treatment of chronic idiopathic myelofibrosis have been authorised in the EU, the COMP concluded that Jakavi is of significant benefit for patients affected by this condition.

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Jakavi still meets the criteria for designation as an orphan medicinal product and that it should remain in the Community register of orphan medicinal products.